Development of breakpoints of carbapenems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in peritoneal fluid

This study aimed to develop breakpoints of carbapenems for intraabdominal infections, based on pharmacokinetics (PK) and pharmacodynamics (PD) at the target site. Imipenem, meropenem, and doripenem were each administered to 8-11 patients before abdominal surgery, and venous blood and peritoneal fluid samples were obtained. The drug concentrations in plasma and peritoneal fluid were determined and analyzed using population pharmacokinetic modeling. Using the pharmacokinetic model parameters, a Monte Carlo simulation was performed to estimate the probabilities of attaining the bacteriostatic and bactericidal targets (20% and 40% of the time above the minimum inhibitory concentration [MIC], respectively) in peritoneal fluid. The bacteriostatic and bactericidal breakpoints were defined as the highest MIC values at which the bacteriostatic and bactericidal probabilities in peritoneal fluid were 80% or more. The breakpoints for the minimum and maximum approved dosages of each drug were identical for imipenem, meropenem, and doripenem, and some of these values varied with dosing interval and infusion time. Site-specific PK-PD-based breakpoints are proposed here for the first time, and should help us to select appropriate carbapenem regimens for intraabdominal infections.     

Acquisition of antimicrobial-resistant variants in repeated infections caused by Pseudomonas aeruginosa revealed by whole genome sequencing

Pseudomonas aeruginosa, responsible for serious nosocomial-acquired infections, possesses intrinsic antibiotic resistance mechanisms and commonly exhibits multidrug resistance. Here, we report the evolving resistance profiles of strains isolated from the sputum of a patient being treated for repeated P. aeruginosa infections following cancer resection. Whole genome sequencing of six isolates obtained over a 2-month period revealed two key single nucleotide polymorphisms in the mexR and gyrB genes that affected efflux pump expression and antimicrobial resistance.     

Spontaneous regression of essential thrombocythemia with MPL mutation on menopause

Essential thrombocythemia (ET) is a subtype of myeloproliferative neoplasms. Approximately half of the patients with ET harbor a gain-of-function mutation in the JAK2 gene (JAK2-V617F), a small percentage have mutations in codon 515 of MPL (thrombopoietin receptor) gene, and the rest have neither mutation. Pregnancy is a rare complication of ET, and it has been reported that the number of blood platelets falls with pregnancy in ET patients and the number of blood platelets increases again after a delivery and this phenomenon is observed in JAK2-V617F-positive and JAK2-V617F-negative patients. We report the first case of an ET patient with MPL mutations, whose platelet count improved with the onset of menopause, not pregnancy, and the MPL mutation also simultaneously disappeared.     

Sociogeographic Variation in the Effects of Heat and Cold on Daily Mortality in Japan

Background

Ambient temperature affects mortality in susceptible populations, but regional differences in this association remain unclear in Japan. We conducted a time-series study to examine the variation in the effects of ambient temperature on daily mortality across Japan.

Methods

A total of 731 558 all-age non-accidental deaths in 6 cities during 2002–2007 were analyzed. The association between daily mortality and ambient temperature was examined using distributed lag nonlinear models with Poisson distribution. City-specific estimates were combined using random-effects meta-analysis. Bivariate random-effects meta-regressions were used to examine the moderating effect of city characteristics.

Results

The effect of heat generally persisted for 1 to 2 days. In warmer communities, the effect of cold weather lasted for approximately 1 week. The combined increases in mortality risk due to heat (99th vs 90th percentile of city-specific temperature) and cold (first vs 10th percentile) were 2.21% (95% CI, 1.38%–3.04%) and 3.47% (1.75%–5.21%), respectively. City-specific effects based on absolute temperature changes were more heterogeneous than estimates based on relative changes, which suggests some degree of acclimatization. Northern populations with a cool climate appeared acclimatized to low temperature but were still vulnerable to extreme cold weather. Population density, average income, cost of property rental, and number of nurses appeared to influence variation in heat effect across cities.

Conclusions

We noted clear regional variation in temperature-related increases in mortality risk, which should be considered when planning preventive measures.Key words: heat, cold, mortality, time-series, distributed lag     

Renal Dysfunction is an Independent Risk Factor for Rebleeding After Endoscopic Hemostasis in Patients with Peptic Ulcer Bleeding

BackgroundDespite the progress in endoscopic hemostasis and pharmacological treatment, the mortality rate of peptic ulcer bleeding remains at 5–10%. Rebleeding after peptic ulcer bleeding is believed to be a risk factor for mortality. This study aimed to evaluate whether renal dysfunction is a predictor of rebleeding after endoscopic hemostasis in patients with peptic ulcer bleeding.Methods: In this retrospective study, consecutive patients with peptic ulcer bleeding who underwent endoscopic hemostasis at our Hospital from January 2010 to December 2018 were enrolled. The relationship between rebleeding within 30 days after endoscopic hemostasis and the patients’ admission and endoscopic characteristics were analyzed using univariate and multivariate regression models.ResultsOut of 274 patients with peptic ulcer bleeding, 17 (6.2%) patients experienced rebleeding. In the analysis of the patients’ admission characteristics, estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² was an independent risk factor for rebleeding (odds ratio 4.77, 95% confidence interval 1.168-18.211, p = 0.03). Patients with eGFR < 15 mL/min/1.73 m² with or without hemodialysis had the highest rebleeding rate at 36.8%. With respect to endoscopic characteristics, the rate of rebleeding was associated with combination therapy (p < 0.0001) and active bleeding (p = 0.03).Conclusion: Renal dysfunction might be an independent risk factor for rebleeding after endoscopic hemostasis in patients with peptic ulcer bleeding.     

Streptococcus thermophilus extends lifespan through activation of DAF-16-mediated antioxidant pathway in Caenorhabditis elegans

Streptococcus thermophilus bacteria, which are widely used as fermented starter for dairy production, exert various beneficial health effects. Nevertheless, even though pro-longevity effects of various probiotics have been reported, no report has described Streptococcus thermophilus effects on longevity. This study was conducted to evaluate Streptococcus thermophilus effects on lifespan extension and to elucidate the Streptococcus thermophilus-mediated longevity mechanism using Caenorhabditis elegans worms as a model animal. They were fed standard food (Escherichia coli OP50) or Streptococcus thermophilus from the young adult stage. Feeding with Streptococcus thermophilus, compared to Escherichia coli OP50, to Caenorhabditis elegans extend the lifespan, reduced lipofuscin accumulation, and maintain vigorous locomotion. Feeding with Streptococcus thermophilus did not alter the worm growth curve or the offspring number, indicating that the Streptococcus thermophilus-mediated lifespan extension is not attributable to caloric restriction. The qRT-PCR data showed that Streptococcus thermophilus increased the expression of daf-16 and some of its downstream antioxidant genes. Furthermore, the pro-longevity effects of Streptococcus thermophilus were decreased in loss-of-function mutant of daf-16. Results show that Streptococcus thermophilus extends the lifespan of Caenorhabditis elegans through DAF-16-mediated antioxidant pathway activation.     

Differences in cerebral metabolic impairment between early and late onset types of Alzheimer's disease

Hypercortisolemia is thought to be a marker of the stress response following stroke. The aim of this study was to investigate the prevalence and prognostic significance of hypercortisolemia. The circadian variation of cortisol level and the relationship between serum cortisol levels and other stress, inflammatory, and haemostatic markers were also investigated. Seventy consecutive patients with their first ischemic stroke and 24 age- and sex-matched controls were included in the study. Serum cortisol levels (at 6:00 AM, 10:00 AM, 6:00 PM, and 10:00 PM), 24-h urine catecholamine excretion, beta-thromboglobulin levels, and other standard biochemical and haematological parameters were measured on the first day of hospitalisation and in control subjects. Outcome measures used the Barthel Index at Day 30, as well as 30- and 90-day mortality rates. Hypercortisolemia, defined as at least two of the four measurements above the normal range of serum cortisol levels (i.e. >618 nmol/l from the morning samples and >460 nmol/l from the evening samples) was found in 25 (35.7%) of the acute stroke patients and in 3 (12.5%) of the controls (p<0.05). Hypercortisolemia was associated with older age, greater severity of neurological deficit, larger ischemic lesions on CT, and worse prognoses (p<0.05). The study did not find a correlation between serum cortisol levels and other markers of the stress response such as catecholamines excretion and glucose levels. A significant correlation between serum cortisol levels and some markers of the inflammatory response, such as fever, fibrinogen level, white blood cell (WBC) count, and beta-thromboglobulin level, was established in stroke patients. Prognostic significance of hypercortisolemia in acute stroke patients seems to be related to the inflammatory response rather than to the stress response.     

The function of the vaccinia hemagglutinin in the proteolytic activation of infectivity

The vaccinia virus hemagglutinin (HA) has specific affinity for the structural protein, VP37K. The nature of this affinity and its relationship to the function of the HA were analyzed using HA mutants. The VP37K reactive site of the HA molecule is located in its transmembrane region, and the vaccinia virus HA associates with the viral particle via the VP37K-HA affinity. The viruses possessing an HA with fusion inhibitor activity were largely of the low infectivity form, whereas the viruses that associated mutant HAs defective in the activity were of the high infectivity form. D1 mutant virus does not produce HA. When it was incubated with the HA of the IHD-J strain, the HA associated with the virus particle. The HA-loaded D1 mutant virus acquired a high affinity not only for chick erythrocytes but also for KB and Vero cells. At the same time, the infectivity for Vero cells was decreased. The original high infectivity was recovered by treatment with trypsin. The virion-associated vaccinia HA has two functions; the HA protects the infectivity of the virus by the fusion inhibitor activity and exhibits affinity against host cells. Vaccinia virus first adsorbs to the cell via HA, and then proteolysis of the HA activates the second adsorption site which seems to be the fusogenic site of the virus. Proteolytic activation represents removal of the fusion inhibitor activity of the HA.